Stimulants

1. Stimulants Charles Dackis, M.D. University of Pennsylvania - Center for Studies in Addiction

2. Stimulants Cocaine Methamphetamine Dextroamphetamine Methylphenidate Others

3. Cocaine History The leaf of the coca plant has been chewed for thousands of years

4. Cocaine History Coca wine had medicinal as well as recreational uses.

5. Cocaine History Celebrity endorsements were common then as they are now. There was little if any perceived risk.

6. Cocaine History Cocaine found its way into a number of different products

7. Cocaine History - A Household Drug Coca Cola originally contained 10 mg of cocaine It was sold in “dope shops”

8. Cocaine Epidemiology Perceived Risk & Supply The key determinants of stimulant epidemics Stimulant “epidemics” driven by low perceived risk and increasing supply, occurred initially with cocaine, later with amphetamine, and again with cocaine in the 1980s. Education can address perceived risk but law enforcement efforts to limit supply have not been particularly successful

9. Cycle of Cocaine Addiction This addiction has biological, behavioral & psychological aspects Cocaine Use EUPHORIA Positive Reinforcement Brain Reward Neuroadaptations Cocaine Seeking Behavior CRAVING Negative Reinforcement Treatment interventions are designed to reduce euphoria & craving

10. Toxicity Cocaine is the most common illicit drug mentioned in ER reports.

11. Toxicity Toxic effects of cocaine result from: • Vasospasm (MI, CVA) • Electrophysiological effects • Seizures • Cardiac arrhythmias • Hypertension (bleeds)

12. Toxicity Cardiac complications of cocaine use: • Angina • Myocardial infarction • Cardiomyopathy • Myocarditis

13. Toxicity Other medical problems: • Hyperpyrexia • Intestinal ischemia • Renal failure • Perforated nasal septum • Low birth weight, spontaneous abortion • Psychosis/Depression/Anxiety

14. Amphetamine Toxicity Methamphetamine • Overtaking cocaine on the West Coast • Significantly more neurotoxicity than cocaine Prescription Stimulants for obesity • Short-term adjuncts • Long-term abuse liability (Adderall) ADD

15. Toxicity: Cocaine Use with Alcohol and Heroin • Cocaine & alcohol • Most common cocaine combination • Reduces anxiety • Cocaethylene is psychoactive and cardiotoxic • Intravenous cocaine & heroin (speedball) • Enhanced euphoria positive effects of both drug • Reduction of unpleasant cocaine effects • Medical complications associated with IV use

16. Clinical Syndrome Cocaine Euphoria Cocaine-Induced Craving Cue-Induced Craving Stress-Induced Craving Baseline Craving Cocaine Withdrawal Hedonic Dysregulation Hypofrontality These clinical components occur at different time points during active addiction and recovery Their psychological, behavioral and neurochemical aspects that can be targeted by psychosocial and pharmacological interventions

17. Dynamic Cycle of Cocaine Addiction + Cocaine Cocaine Euphoria Positive Reinforcement Activated Reward Pathways DA/Glutamate Cocaine Administration Drug-Seeking Behavior Failed Impulse Suppression Multiple Risks/Hazards Reward Dysregulation Cocaine Withdrawal DA/Glutamate Dynorphin/GABA - Cocaine Craving Negative Reinforcement DA/Glutamate Loss of Control Denial / Poor Decision-Making Hypofrontality / Low D2 Reduced Gray Matter Density Cocaine Cues Limbic Activation DA/Glutamate Stress

18. Cocaine Euphoria Brief duration Gives way to craving in minutes (even when levels are still elevated) Lack of satiation - multiple doses Binge pattern use Intensely rewarding Animals self-administer till death Patients obsessed with euphoria Distinctive features v. heroin/alcohol Manic-like, racing thoughts, energy, vigilance Psychomotor activation, environmental focus

19. Neurobiology of Cocaine Euphoria DA Neurotransmission Imaging studies demonstrated correlate cocaine euphoria with: Rate by which cocaine effectively binds the DAT DA release D2 binding Glutamate neurotransmission Mice devoid of mGluR5 receptors do not self-administer cocaine - despite NAc DA levels Cocaine increases DA and glutamate levels Euphoria likely requires the activation of both systems

20. Routes of Administration Oral Intrapulmonary By-passes the venous system Intranasal Intravenous Intrapulmonary

21. Cocaine Craving Cocaine-induced craving Glutamate depletion Cue-induced craving DA/glutamate activation Stress-induced craving CRF, NE & DA/glutamate activation Baseline craving DA/glutamate depletion?

22. Cocaine-Induced Craving Demonstrated under controlled conditions Craving after cocaine exceeds baseline craving Patients feel worse within minutes of cocaine use Fuels a characteristic binge use pattern Increases dangerous exposure to the drug Glutamate depletion & cocaine-induced reinstatement Cocaine depletes NAc glutamate N-acetylcysteine (normalizes glutamate) N-acetylcysteine obliterates cocaine reinstatement Glutamate-enhancing drugs may dampen cocaine-induced craving

23. Cue-Induced Cocaine Craving • Clinically pernicious - leads directly to relapse • Persistent (weeks, months, years) • Compelling • Often unpredictable • Difficult to avoid • Involves reward-related memory (LTP) Might cue-induced craving respond to pharmacotherapy?

24. Neuroimaging Studies of Cue Craving Robust limbic activation (PET & fMRI) - many studies Amygdala Glutamatergic frontal regions Craving intensity correlates with limbic activation Same regions activated by sexually explicit videos (Cocaine hijacks sex reward circuits) Baclofen (GABAB agonist) may reverse cue craving Limbic activation provides a means of testing anti-craving medications in the laboratory under controlled conditions

25. Stress-Induced Cocaine Craving Patients often relapse during periods of stress Traditionally seen as a wish to “escape” via cocaine Purely psychological reaction Biological basis suggested by animal studies Stress-induced reinstatement CRF release Norepinephrine release Might stress-induced craving respond to CRF or norepinephrine antagonists?

26. Stress-Induced Cocaine Craving CRF activates reward circuits in cocaine addicted animals Stress releases CRF in all animals Stress only releases DA in cocaine treated animals DA is released via CRF-induced elevation of glutamate in the VTA DA release is required for stress-induced reinstatement Agents that block DA and/or glutamate might dampen stress-induced craving DA/glutamate antagonists (or GABA agonists) might dampen stress-induced craving?

27. Cocaine Withdrawal • Anergia • Depression • Bradycardia • Hyperphagia • Hypersomnia • Poor concentration • Psychomotor retardation • Cocaine withdrawal is not medically dangerous but severe withdrawal curiously predicts poor clinical outcome

28. Cocaine WD Predicts Poor Outcome Several studies report that the presence of severe cocaine withdrawal symptoms at baseline predicts poor clinical outcome Craving Hedonic Dysregulation Is cocaine withdrawal just the tip of the iceberg? WD

29. Cocaine-Induced Neuroadaptations Reversing cocaine-induced neuroadaptations represents another viable pharmacological strategy Clinical components that may respond include: Baseline craving, cocaine withdrawal, hedonic dysregulation, and even denial . . . Principle cocaine-induced neuroadaptations include: DA depletion Glutamate depletion GABA/dynorphin upregulation A role for DA/glutamate agonists or GABA/dynorphin antagonists

30. Glutamate Dysregulation by Cocaine Reduced NAc glutamate levels (Keyes 1998, Bell 2000, Hotsenpiller 2001,Kalivas 2005) Reduced NAc Glu synaptic strength (Swanson 2001, Thomas 2001) Downregulated mGluR2/3 autoreceptors (compensatory response?)(Xi 2002) Cocaine acutely increases but chronically inhibits glutamate activity

31. Dopamine Dysregulation by Cocaine Cocaine-Addicted Patients Reduced presynaptic DA activity (PET) 6-Fluorodopa (Wu 1997), Raclopride (Volkow 1997) Reduced [DA] at autopsy (Wilson 1996, Little 1996, 1999) Reduced D2 availability (Volkow 1999) Hyperprolactinemia (Dackis 1985, Mendelson 1988, Lee 1990, Teoh 1990* Satel 1991, Vescovi 1992, Kranzler 1992*, Elangovan 1996 Patkar 2002*)*Associated with poor clinical outcome DA tone on electroretinography (Roy 1997, Smelson 1998) Cocaine acutely increases but chronically inhibits DA activity

32. DA-Enhancing Agents for Cocaine Dependence Two recent controlled studies reported efficacy in cocaine dependence with DA-enhancing agents: Modafinil (400 mg/day; n = 62)(Dackis et al, 2005) - Enhances DA through DAT blockade Disulfiram (250 mg/day; n = 121)(Carroll et a; 2004) - Enhances DA by inhibiting dopamine -hydroxylase Conversely, the DA antagonist olanzapine destabilized cocaine-dependent subjects (Kampman 2003)

33. Functions Ascribed to Prefrontal Cortex • Decision-making • Weighing of risks vs. rewards • Assigning emotional valence to stimuli • Suppressing limbic impulses • Goal-directed behaviors Might PFC dysfunction contribute to denial? Is there a role for agents that increase PFC activity?

34. Denial: The Hallmark of Cocaine Dependence • Poor decision making • Impaired ability to weigh risks against benefits • Dangerous risk tolerance • Poor impulse suppression • Cocaine becomes the first priority Denial, traditionally viewed as purely psychological, may result in part from prefrontal cortical dysfunction

35. Natural History - Relapse and Progression • Increased dose and frequency • Change of route of administration • Development of tolerance • Development of withdrawal symptoms • Medical and psychiatric complications • Functional impairment

36. Progressive Complications of Cocaine Dependence • Death(MI, hyperthermia, hemorrhage, violence) • Medical(cardiac, seizures, stroke, renal) • Psychiatric(psychosis, depression, panic, suicide) • Legal(incarceration: possession, dealing, prostitution, theft) • Family(child neglect, violence, divorce) • Occupational(job loss: absenteeism, poor performance) • Financial(drug procurement, loss of income) Denial shields patients from their predicament

37. Treatment of Stimulant Dependence • Provider requires specialized knowledge • Patient requires motivation • Patient may not want to stop using drugs • Attitude/Compliance is important • Recovery requires sacrifice • Clinical course involves relapse/progression

38. Assessment & Treatment • Comprehensive Assessment • Medical • Psychiatric • Psychiatric • Psychosocial • Abstinence Initiation • Readiness for change • Relapse Prevention • Different levels of care • Inpatient, IOP, outpatient

39. Importance of Collateral Information “Substance abusers are reluctant to disclose sensitive personal information” (They lie)

40. Sources of Collateral Information Laboratory Testing Physical Examination Family\Informant Interviews Past Medical Records

41. Treatment Modalities • Intervention • Abstinence-based AA/NA model • Individual, group, & family therapy • Pharmacotherapy

42. Treatment of cocaine dependence - Psychosocial Individual drug counseling is effective

43. Treatment of cocaine dependence - Psychosocial Voucher treatment improves short-term abstinence (Higgins, 1994)

44. Treatment of Stimulant Dependence - Medications There are no medications with proven efficacy for stimulant dependence

45. Treatment of cocaine dependence - Medications • Possible medications include: • Modafinil - blocks euphoria • Propranolol - reduces stress • Baclofen - reduces cue-craving • Topiramate - relapse prevention • Disulfiram - reduces alcohol use, increases DA • Cocaine vaccine - blocks euphoria

46. Distinct Clinical Components of Cocaine Dependence Cocaine Euphoria Cocaine-Induced Craving Cue-Induced Craving Stress-Induced Craving Baseline Craving Cocaine Withdrawal Hedonic Dysregulation Hypofrontality These clinical components occur at different time points and could be targeted by specific pharmacotherapies It is very unlikely that a single medication could treat each of these clinical phenomena

47. Conceptualizing Pharmacotherapy Abstinence Initiation Relapse Prevention (Cue Craving) DA/Glutamate Enhancing Agents Modafinil (glutamate-enhancing)* Amantadine (releases DA)* Disulfiram (brain DA; DBH)* DA/Glutamate Inhibiting Agents Ondansetron (DA release) Tiagabine (GABA uptake) Baclofen (GABAB agonist)* Topiramate (GABA, AMPA blocker)* *Positive findings in DB trials

48. Modafinil Promotes Cocaine Abstinence Study Week Longitudinal GEE models showed a significant main effect for cocaine abstinence in the modafinil group (odds ratio = 2.41, 95% CI 1.09-5.31, p = 0.03) Dackis et al.Neuropsychopharmacology, 2005

49. Modafinil Attenuates Cocaine Euphoria Modafinil (4 days: LD = 200 mg/day, HD = 400 mg/day) reduced euphoria ratings after IV cocaine (p = 0.02) Dackis et al: Drug and Alcohol Dependence, 2003

50. Treatment of Cocaine Dependence - Medications Disulfiram is Effective in Cocaine Dependent Patients With and Without Alcohol Dependence (*Carroll, 1998, ** George, 1999)